The present invention relates to the use of formulations from Crataegus for the preparation of pharmaceutical preparations or food supplements for the prophylaxis and/or treatment of tumour diseases, the formulations substantially comprising constituents of Crataegus which are soluble in polar solvents. The invention furthermore relates to the use of Crataegus plant parts for the preparation of infusions. Compositions for the prophylaxis and/or treatment of tumour diseases are furthermore included.
In spite of advances in modern medicine, tumour diseases, i.e. malignant neoformations, still count among the most frequent diseases with in most cases very poor courses of the disease and predominantly fatal consequences. Undesirable side effects narrow the use of currently available medicaments in prophylaxis and treatment. A large number of active chemotherapeutics (cytostatics and cytotoxics), such as e.g. 5-fluorouracil or methotrexate, have so far been developed. However, the disadvantage of chemotherapeutics lies in the potent side effects. The side effects are to be attributed to the fact, inter alia, that the active compounds employed in chemotherapy also have a cytostatic and/or cytotoxic action on xe2x80x9chealthyxe2x80x9d cells, i.e. cells which proliferate normally. This leads in particular to damage to cells which normally divide frequently, such as e.g. keratinocytes, fibroblasts, endothelial and epithelial cells, stem cells of blood formation (haematopoietic system) and gametes, with the consequence of undesirable actions, such as e.g. hair loss (alopecia), damage to mucous membranes (mucosititis, intestinal ulcerations), suppression of blood formation (myelosuppression with the consequence of anaemia, infections and bleeding complications) and infertility. This limits the applicability of the currently available chemotherapeutics in treatment and prohibits their use in prophylaxis of neoplastic diseases.
The object of the present invention is therefore to provide a composition, in particular a pharmaceutical preparation or food supplement, for the prophylaxis and/or treatment of tumour diseases which does not have the side effects mentioned for the chemotherapeutics known in the prior art. In particular, an object of the present invention is to provide a composition which, in contrast to the chemotherapeutics currently used, has no effect or only a mild cytostatic or cytotoxic effect on normally proliferating cells.
The object is achieved according to the invention in that a formulation from Crataegus which substantially comprises constituents of Crataegus which are soluble in polar solvents (including polar protic solvents) is used for the preparation of a composition for the prophylaxis and/or treatment of tumour diseases (neoplastic diseases).
Formulations which substantially comprise constituents which are soluble in polar solvents are therefore to be understood as meaning those formulations which are obtainable employing processes with which polar constituents of Crataegus are obtained. The possible processes for the preparation of these formulations here are mentioned below by way of example. The term xe2x80x9cpolar solventsxe2x80x9d in the context of the invention is generally understood as meaning aqueous and non-aqueous solvents, the latter group including, in particular, organic nitrogen and oxygen compounds, but not carbon disulphide, carbon tetrachloride and saturated hydrocarbons.
In the context of the present invention, the composition can be pharmaceutical preparations, medicaments, remedies, food supplements, dietary supplements, botanics, herbal remedies, additives to food supplements or to foodstuffs and the like, such as nutritive additives, teas or the like, in particular depending on the specification according to medical preparations law.
According to the invention, it has been found, surprisingly, that formulations which substantially comprise constituents of Crataegus which are soluble in polar solvents are particularly suitable for the prophylaxis and/or treatment of tumour diseases without showing the undesirable side effects of the chemotherapeutics known from the prior art.
Crataegus extracts have already been employed in folk medicine for a long time for the treatment of cardiovascular diseases, and have since also been recognized by science as effective for these diseases.
Crataegus is widespread throughout the world in the temperate climate zones on the northern and southern hemispheres and in the high mountains of the tropics (R. Kaul, xe2x80x9cDer Weixcex2dorn: Botanik, Inhaltsstoffe, Qualitxc3xa4tskontrolle, Pharmakologie, Toxikologie und Klinik [The Hawthorn: Botany, constituents, quality control, pharmacology, toxicology and clinical aspects]xe2x80x9d, 1st edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart 1998). It is the largest genus of the Maloideae (Pomoideae) a sub-family of the Rosaceae. The genus Crataegus includes approx. 100 to 200 true species (I. Bauer and U. Hoelscher, xe2x80x9cCrataegusxe2x80x9d in R. Hxc3xa4nsel, K. Keller, H. Rimpler, G. Schneider (editors), Hagers Handbuch der Pharmazeutischen Praxis [Hagers handbook of pharmaceutical practice], volume 4, 5th edition, Springer verlag, Berlin 1992, 1040-1062). In Central Europe, Crataegus laevigata (synonym: Crataegus oxyacantha) and Crataegus monogyna and hybrids thereof are chiefly encountered; these are also the predominant Crataegus species in the western Mediterranean region and North Africa, while in the eastern Mediterranean region and Eurasia Crataegus pentagyna and Crataegus nigra are the preferred species, and in the eastern part of Eurasia, in addition to C. laevigata and C. monogyna, C. curvisepala and C. azarolus also grow. C. cuneata and C. pinnatifida are employed medicinally in Japan, China and adjacent regions, while in North America C. berberifolia, C. aestivalis, C. chrysocarpa, C. crus-galli and C. pruinosa are also taken for cardiovascular symptoms, at least in folk medicine. Most studies of the constituents carried out on C. laevigata have shown that all the plant parts of Crataegus contain a large number of constituents from the most diverse groups of substances (cf. F. Hoffmann, Pharmaceutica Acta Helvetiae 36 (1961) 30-39; B. Lay xe2x80x9cZur Chromatographie von Pimpinella major, Panax Ginseng, Crataegus oxyacantha, Tussilago farfara und Mentha piperita [The chromatography of Pipinella major, Panax ginseng, Crataegus oxyacantha, Tussilago farfara and Mentha piperita]xe2x80x9d, dissertation 1965, Ludwig-Maximilians University Munich; N. Nikolov et al., xe2x80x9cRecent investigations of Crataegus flavonoidsxe2x80x9d in L. Farkas, M. Gxc3xa1bor, F. Kxc3xa1llay, H. Wagner (editors), Elsevier Scientific Publishing Company, Amsterdam 1982, 325-344; M. Schxc3xcssler, xe2x80x9cIn-vitro-Untersuchungen zur Pharmakologie von Flavonoiden aus den offizinellen Crataegus Spezies und ihre analytische Charakterisierung [In vitro studies of the pharmacology of flavonoids from the officinal Crataegus species and their characterization by analysis]xe2x80x9d, dissertation 1995, Philipps-University Marburg; R. Kaul, xe2x80x9cDer Weixcex2dorn [The Hawthorn]xe2x80x9d, loc. cit.).
Crataegus has a distinct cardiovascular action. The numerous studies are summarized in detail by Ammon et al. (H. P. T. Ammon et al., xe2x80x9cCrataegus, Toxikologie und Pharmakologie, Teil I: Toxizitxc3xa4t [Crataegus, toxicology and pharmacology, part I: Toxicity]xe2x80x9d, Planta medica 43 (1981) 105-120; H. P. T. Ammon et al., xe2x80x9cCrataegus, Toxikologie und Pharmakologie, Teil II: Pharmakodynamik [Crataegus, toxicology and pharmacology, part II: Pharmacodynamics]xe2x80x9d, Planta medica 43 (1981) 209-239; H. P. T. Ammon et al., xe2x80x9cCrataegus, Toxikologie und Pharmakologie, Teil III: Pharmakodynamik und Pharmakokinetik [Crataegus, toxicology and pharmacology, part III: Pharmacodynamics and pharmacokinetics]xe2x80x9d, Planta medica 43 (1981) 313-322; the works of Ammon et al. have also served as a basis for the monograph in Bundesanzeiger [German Federal Gazette] no. 1 of Mar. 1, 1984, amended in Bundesanzeiger [German Federal Gazette] no. 85 of May 5, 1988 and revised by the monograph in Bundesanzeiger [German Federal Gazette] p. 7360 of Jul. 19, 1994 xe2x80x9cCrataegi flos (hawthorn blossom), Crataegi folium (hawthorn leaves), Crataegi folium cum flore (hawthorn leaves with blossom), Crataegi fructus (hawthorn fruit)xe2x80x9d). The approval of the drug attests positively inotropic, chronotropic, dromotropic and negatively bathmotropic properties and an increase in coronary and myocardial circulation for Crataegus. Indications are mild formsart failure and of cardiac arrhythmia.
The antiproliferative properties of individual flavonoids, from which quercetin and luteolin-7-glucoside are also found in Crataegus in smallest amounts, were investigated in a work by Fotsis et al. (Cancer Research 57 (1997) 2916-2921). It was found that quercetin and luteolin-7-glucoside have an inhibiting effect on the proliferation of human neuroblastoma and breast carcinoma cells. However, at the same time it was also found that, like other chemotherapeutics already known, it also inhibits the proliferation of human fibroblasts, keratinocytes and endothelial cells, i.e. that is to say physiologically proliferating cells which occur naturally in the human and animal organism. The particular half-maximum concentrations required in each case for inhibition here were in the same range for the tumour cells and the physiological cells. This means that the use of flavonoids as individual substances in active concentrations has the same undesirable effects as have been mentioned above for all known chemotherapeutics.
In the context of the present invention, it has now been found, surprisingly, that formulations of Crataegus which substantially comprise constituents (i.e. mixtures of constituents) of above-ground (aerial) Crataegus plant parts which are soluble in polar solvents have a cytostatic and/or cytotoxic action against tumour cells but do not show the antiproliferative action observed for the individual substances described, i.e. isolated flavonoids, on physiologically dividing cells (and the resulting undesirable side effects, monograph in Bundesanzeiger [German Federal Gazette] p. 7360 of Jul. 19, 1994). In particular, long-term, high-dosed administration of such Crataegus formulations also does not lead to damage of cells which physiologically divide frequently, such as, in particular, e.g. keratinocytes, fibroblasts, endothelial and epithelial cells, stem cells of blood formation (haematopoietic system) and gametes (I. Bauer and U. Hoelscher, xe2x80x9cCrataegusxe2x80x9d, loc. cit.).
Cytotoxic effects of hexane extracts from Crataegus and of triterpene-enriched fractions obtained therefrom have been described in works by Saenz et al. (Zeitschrift fxc3xcr Naturforschung 52c (1997) 42-44). The authors attributed the cytotoxic action to triterpene compounds.
As has been shown in the context of the present invention, the formulations from Crataegus used according to the invention surprisingly have a broader action spectrum than hexane extracts. While hydrophobic hexane extracts show no or only a mild cytotoxic action against a large number of various tumour cell lines, the formulations which substantially comprise constituents which are soluble in polar solvents have a cytostatic and/or cytotoxic action against all the tumour cell lines investigated, the inhibition of cell proliferation being significantly more pronounced in the formulations of the present invention.
In the context of the present invention, all Crataegus species, in particular those mentioned above, are possible for the preparation of pharmaceutical preparations or of food supplements, it being possible for all the above-ground (aerial) plant parts, in particular leaves (folii), blossom (flores), fruit (fructus) and mixtures thereof (e.g. folium cum flores), to be used.
The formulations can be prepared by all the processes known to the expert which are employed for the preparation of phytopharmaceuticals, such as e.g. pressing (pressed juice), maceration, agitation maceration, shaking maceration, digestion, agitation digestion, (exhaustive) percolation, Soxhlet extraction, evacolation, recolation, fluidized extraction, Ultra-Turrax extraction, ultrasonic extraction, processes with concentration of first runnings and/or after-runnings, counter-current processes and also more recent processes, such as e.g. extraction with liquids or supercritical liquids or gases, without or with subsequent purification, such as e.g. by filtration, decanting, sedimentation, centrifugation, adsorption, precipitation, chromatography etc. (cf. e.g.: J. Ploschke, xe2x80x9cExtraktion [Extraction]xe2x80x9d in E. Nxc3xcrnberg, P. Surmann (editors), Hagers Handbuch der Pharmazeutischen Praxis [Hagers handbook of pharmaceutical practice], volume 2, 5th edition, Springer Verlag, Berlin 1991, 403-411; J. Ziegenmeyer, xe2x80x9cZubereitungen aus Pflanzen und Drogen [Formulations from plants and drugs]xe2x80x9d in E. Nxc3xcrnberg, P. Surmann (editors), Hagers Handbuch der Pharmazeutischen Praxis [Hagers handbook of pharmaceutical practice], volume 2, 5th edition, Springer Verlag, Berlin 1991, 1015-1032; R. Voigt, xe2x80x9cDurch Drogenextraktion gewonnene Arzneiformen [Medicament forms obtained by drug extraction]xe2x80x9d in Pharmazeutische Technologie [Pharmaceutical technology], 8th edition, Ullstein Mosby Verlag, Berlin 1995, 525-552); monograph xe2x80x9cWeixcex2dornfluidextrakt [Hawthorn fluid extract]xe2x80x9d Deutsches Arzneibuch [German Pharmacopoeia] 10 (DAB 10), 2nd supplement of 1993, official edition, Deutscher Apotheker Verlag, Stuttgart; monograph xe2x80x9cCrataegi Extractum Siccum Normatumxe2x80x9d of Pharmacopoeia Helvetica [Swiss Pharmacopoeia] VII). In the context of the present invention, these preparation processes can be carried out both on a larger xe2x80x9cindustrialxe2x80x9d scale, i.e. e.g. by a manufacturer of medicaments, and in the context of individual formulations, e.g. by the pharmacist. The formulation of infusions is also included according to the invention, the abovementioned Crataegus plant parts being employed for this.
According to a particular embodiment of the invention, the Crataegus formulation is an extract obtainable by extraction with water, alcohol, acetic acid, liqueur wine, a supercritical gas, a supercritical liquid or mixtures thereof as the extraction agent.
According to another embodiment of the invention, the formulation is a pressed juice. It has been found that pressed juices of Crataegus which substantially comprise hydrophilic constituents (cf. I. Bauer and U. Hoelscher, xe2x80x9cCrataegusxe2x80x9d in R. Hxc3xa4nsel, K. Keller, H. Rimpler, G. Schneider (editors), Hagers Handbuch der Pharmazeutischen Praxis [Hagers handbook of pharmaceutical practice], volume 4, 5th edition, Springer Verlag, Berlin 1992, 1040-1062 and J. Ziegenmeyer, xe2x80x9cZubereitungen aus Pflanzen und Drogen [Formulations from plants and drugs]xe2x80x9d in E. Nxc3xcrnberg, P. Surmann (editors), Hagers Handbuch der Pharmazeutischen Praxis [Hagers handbook of pharmaceutical practice], volume 2, 5th edition, Springer Verlag, Berlin 1991, 1015-1032) are also particularly suitable. Pressed juices are preferably prepared from the above-ground (aerial) plant parts, preferably the fruit.
If pressed juices are used according to the invention, they can either be employed directly as a pharmaceutical preparation or as a food supplement, or can be diluted with liquids or solutions suitable for this purpose, preferably water, aqueous salt solutions, ethanol, syrups or wines (medicinal wines) or mixtures thereof. Further additives familiar to the expert can moreover be added, e.g. for galenical reasons, for preservation, for improving the smell, taste and appearance, for improving the particular pharmacokinetics or pharmacodynamics sought or for other reasons. The pressed juices can also be concentrated by processes known to the expert.
According to a particular embodiment of the invention, the use of extracts obtainable with polar extraction agents, i.e. with extraction agents which transfer substantially polar constituents from Crataegus into the extract, is preferred. In this connection, aqueous and/or alcoholic extracts and extracts prepared with supercritical liquids or gases under conditions which transfer predominantly polar constituents from the plant parts into the extract are particularly preferred. In the context of the present invention, any alcohol which is water-miscible and gives an aqueous solution which leads, as the extraction agent, to the composition of the extracts which is used according to the invention can be employed. In the case of alcoholic extracts, possible extraction agents are, in particular, lower aliphatic alcohols having one to ten, preferably one to six C atoms, in particular alcohols from the group consisting of methanol, ethanol, propanol, butanol, pentanol and/or hexanol, including their isomers and mixtures thereof. The fluid extracts can be obtained from above-ground (aerial) plant parts e.g. with lower alcohols (preferably C1-C6), with water, with aqueous alcoholic solutions, with dilute acetic acid, with liqueur wines or with other extraction agents which transfer polar constituents from the plants into the extract, or can be generated as pressed juice, preferably from fruits.
In addition to water, alcohol(s) and other extraction agents as those which transfer polar constituents from the plants into the extract, the extraction can also be carried out with a mixture of the extraction agents mentioned; a mixture of alcohol and water in particular is the extraction agent, an alcohol/water mixture with a content of 10 to 99 vol. % alcohol being preferred. According to a particularly preferred embodiment of the invention, the extraction agent is an alcohol/water mixture with a content of 15 to 95 vol. % alcohol.
If fluid extracts are used according to the invention, they can be employed either directly as a pharmaceutical preparation or as a food supplement, or be diluted with liquids or solutions suitable for this purpose, preferably water, aqueous salt solutions, ethanol, syrups or wines (medicinal wines) or mixtures thereof. Further additives can moreover be added, e.g. for galenical reasons, for preservation, for improving the smell, taste and appearance, for improving the pharmacokinetics or pharmacodynamics sought or for other reasons. The fluid extracts can also be concentrated by known methods, e.g. to Extractum spissum.
The use of dried extracts which are obtainable by removal (e.g. by evaporation under reduced pressure or other processes familiar to the expert) of the extraction agent (e.g. in the case of fluid extracts) or of the solvent (e.g. in the case of pressed juices) and subsequent drying (such as e.g. by lyophilization, spray drying or other processes familiar to the expert) is furthermore possible in the context of the present invention (cf. J. Ziegenmeyer, xe2x80x9cZubereitungen aus Pflanzen und Drogen [Formulations from plants and drugs]xe2x80x9d, loc. cit. and R. voigt, xe2x80x9cDurch Drogen-extraktion gewonnene Arzneiformen [Medicament forms obtained by drug extraction]xe2x80x9d, loc. cit.). The removal of the extraction agent or solvent is particularly desirable if it is not suitable as such or is suitable to only a very limited extent for administration to humans or animals. The dried extract can be used as such or subsequently dissolved, emulsified, dispersed or suspended again, if desired, in a suitable medium, in particular in a physiologically tolerated liquid, water, aqueous salt solutions, ethanol, wines (medicinal wines) and other solvents which, in particular, convert the polar constituents of the extracts in to a suitable state in respect of the chosen galenics and from the aspect of the pharmacokinetics, or mixtures of the liquids mentioned, being preferred for preparation of the solution, emulsion, dispersion or suspension. For uptake in ethanol, uptake of the dried extracts in aqueous ethanol having a concentration of 15 to 75 vol. % is preferably suitable.
Suitable additives can be admixed to the dried extract used as such or after preparation of a solution, dispersion, emulsion or suspension, e.g. for dilution or for galenical reasons, for preservation, for improving the smell, taste and appearance, for improving the pharmacokinetics or pharmacodynamics sought or for other reasons.
According to the invention, the formulations mentioned can be prepared either individually or in the form of mixtures or combinations of the formulations mentioned, in particular from the plant parts, fluid extracts, pressed juices, dried extracts etc. mentioned. Extracts which have been obtained with various extraction agents and/or from various plant parts, for example, can be mixed with one another here, such as e.g. an ethanolic dried extract from leaves and blossom dissolved in a pressed juice from fruits.
According to a particular embodiment of the invention, the formulation used is an extract which is obtainable by a process in which plant parts of Crataegus are first extracted with a lipophilic (aprotic) solvent, in particular with an apolar aprotic solvent such as e.g. hexane, heptane or the like, and then, in a further step, either a pressed juice is prepared from the plant parts treated in this way or the plant parts treated in this way are treated with one of the abovementioned polar extraction agents, in order to substantially transfer the constituents soluble in these solvents from the plants into the extract. In other words, in the context of the present invention, the formulation can be an extract which is obtainable from Crataegus plant parts which have first been subjected to an extraction with a lipophilic (apolar) extraction agent before the extraction with the polar extraction agent, i.e. in a prior step.
The formulations used according to the invention for the prophylaxis and/or treatment of tumour diseases are preferably standardized in respect of their content of active compound, the so-called indicator substances for the presence according to the invention of constituents which dissolve in polar solvents being flavonoids, preferably hyperoside according to Deutsches Arzneibuch [German Pharmacopoeia] 10, basic edition 1991 (DAB 10) xe2x80x9cWeixcex2dornblxc3xa4tter mit Blxc3xcten [Hawthorn leaves with blossom]xe2x80x9d or DAB 10xe2x80x942nd supplement 1993, xe2x80x9cWeixcex2dornfluidextrakt [hawthorn fluid extract]xe2x80x9d or vitexin or a mixture of vitexin and hyperoside according to Note Technique Pro Pharmacopoea (NTPP) 708/709 xe2x80x9cExtrait d""Aubepinexe2x80x9d [Crataegus extract] (sec) or procyanidines as cyanidine chloride according to Deutscher Arzneimittel Codex [German Pharmaceuticals Codex] 86 (DAC 86), 4th supplement 1992, or epicatechin according to the monograph in Bundesanzeiger [German Federal Gazette] p. 7360 of Jul. 19, 1994.
According to a particular embodiment of the invention, the extracts used according to the invention comprise about 0.1 to 13 wt. %, preferably about 0.2 to 6.5 wt. %, and particularly preferably about 0.24 to 4.0 wt. % or 0.24 to 2.0 wt. % flavonoids and/or about 0.05 to 20 wt. %, preferably about 0.1 to 10.0 wt. %, and particularly preferably about 0.2 to 5.0 wt. % procyanidines (for Crataegus leaves and/or blossom determined according to Bundesanzeiger, loc. cit.; according to a particular embodiment, the extracts from Crataegus fruits comprise about 0.05 to 10 wt. %, preferably about 0.1 to 5.0 wt. %, and particularly preferably about 0.2 to 3.0 wt. % procyanidines determined according to DAC 86, loc. cit.).
In the context of the present invention, the formulations are used for the preparation of compositions, in particular pharmaceutical formulations and food supplements, for the prophylaxis and/or treatment of tumour diseases, i.e. malignant or semi-malignant neoplastic diseases and precancerous stages, in humans and in animals.
The formulations are particularly suitable for the prophylaxis and treatment of tumour diseases from the group consisting of precancerous stages, carcinomas, sarcomas (incl. leukaemias and lymphomas), teratomas, blastomas and mixed tumours; and in turn here, in particular colon carcinomas and rectum carcinomas and other neoplastic diseases of the digestive tract, including its appended organs (in particular of the oral cavity, oesophagus, stomach, intestine, liver, gallbladder and pancreas), of kidney carcinomas and other neoplastic diseases of the urogenital system (here in particular of the ovary, cervix, uterus, bladder, prostate and testes), of osteosarcomas and other sarcomas (in particular fibro-, leiomyo-, rhabdomyo- and liposarcomas and leukaemias and lymphomas) and other neoplastic diseases of the supporting apparatus, of melanomas and other neoplastic diseases of the skin, mucous membranes and their appended organs, of glioblastomas and other neoplastic diseases of the central and peripheral nervous system, including its supporting tissue, and of neoplastic diseases of the respiratory tract (here in particular of the larynx, pharynx, bronchi and alveolar cells), of the breast (mamma), thyroid and parathyroid and of mixed tumours.
The use according to the invention of formulations which chiefly or substantially comprise constituents of Crataegus which dissolve in polar solvents have the advantage that substantial undesirable side effects are as yet unknown for them.
Since no serious side effects are so far known for such Crataegus extracts, the dosage is not critical, so that the extracts can also be concentrated, if appropriate.
In the context of the present invention, in general the dosage of the extracts usually used for cardiovascular diseases, that is to say about 0.1 to 1.8 g dried extract/day or 0.5 to 100 g fluid extract/day or about 0.1 to 1 liter tea/day or about 1.0 to 100 g juice/day, can be chosen for the prophylaxis and/or treatment of tumour diseases. However, because of the good tolerability of Crataegus formulations, which has already been demonstrated in the context of treatment of cardiovascular diseases, an increase in the dosage is conceivable.
The present invention furthermore relates to compositions for the prophylaxis and/or treatment of tumour diseases which comprise an abovementioned formulation which substantially comprises constituents of Crataegus which dissolve in polar solvents, the compositions being either pharmaceutical preparations, food supplements, additives to food supplements or additives to foodstuffs. According to a particular embodiment of the invention, these compositions can also be present in a form for the preparation of infusions, e.g. as teas.
On the basis of the cytostatic and cytotoxic effects shown in the context of the present invention, these formulations open up a new therapeutic use. With the use according to the invention of the formulations, it is therefore possible to supplement or replace the treatment measures which have so far not yet been finally satisfactory against (semi-)malignant neoplastic diseases. Because of their exceptionally good tolerability in particullar, it is possible to use the above-mentioned Crataegus extracts and pressed juices not only in treatment of these diseases, but also in their primary (that is to say already before the occurrence of a disease) and secondary (that is to say to prevent a recurrence or a second tumour after treatment) prophylaxis.
On the basis of their cytostatic or cytotoxic action on (semi-)malignant neoplastic cells/tumours in humans and animals, the formulations from Crataegus are suitable for use in the primary and secondary prophylaxis and the treatment (adjuvantly, palliatively or under certain circumstances also solely as the essential active substance) of (semi-)malignant neoplastic diseases in humans and animals, formulations also in combination with other phytopharmaceuticals or in combination with chemically defined substances, i.e. e.g. with known chemotherapeutics (cytostatics and/or cytotoxics or other pharmaceuticals) or food supplements or with foodstuffs being possible.
The compositions according to the invention can be formulated for external or internal use. For external use, they can be used transdermally or ocularly for application directly to the tumour. Internal use can be enteral or parenteral. If it is parenteral, it can take place, in particular, by inhalation, by infusion, by subcutaneous or intramuscular or intravenous injection, intravaginally, intrauterinally, rectally, intraurethrally or intravesically and by direct injection into the tumour or the affected tissue or organ. The Crataegus formulations used according to the invention are formulated according to the particular chosen form of administration. Possible medicament forms are therefore e.g. inhalation solutions, aerosols, dusts, mists, instant teas, tea formulations, infusions, decoctions or macerations, as well as foams, mixtures, shaking mixtures, pulverulent forms, powders, tablets, coated tablets, granules, capsules (including jacketed and multi-layered tablets or mixed granules), eye medicaments, mucous membrane adhesives, patches, juices, tinctures, wines, lotions, solutions, essences, suspensions, emulsions, pastes, ointments, creams, gels, special bandage coverings, adhesion dressings, suppositories, medicament sticks, pellets or implantable medicament forms (such as pump fillings) etc. Particular galenical formulations such as liposomes or coated tablets, microemulsions and nanoparticles, including galenical formulations which comprise a particularly rapid or delayed release (depot forms) and combinations thereof are also suitable in particular (R. Voigt, xe2x80x9cPharmazeutische Technologie [Pharmaceutical technology]xe2x80x9d, 8th edition, Ullstein Mosby Verlag, Berlin 1995; T. Wimmer et al. xe2x80x9cArzneiformen [Medicament forms]xe2x80x9d in E. Nxc3xcrnberg, P. Surmann (editors), Hagers Handbuch der Pharmazeutischen Praxis [Hagers handbook of pharmaceutical practice], volume 2, 5th edition, Springer Verlag, Berlin 1991, 622-1047).
The use of Crataegus plant parts, e.g. in the form of tea, for the preparation of infusions is furthermore possible in the context of the present invention.
In the context of the present invention, the formulations which substantially comprise constituents of Crataegus which are soluble in polar solvents can be employed either as a pharmaceutical preparation (i.e. as a medicament) or as a food supplement.
The invention is described below with the aid of examples.
The actions of various extracts from plants of the species Crataegus on the growth properties and the survival of tumour cells were investigated in the examples described below.